JP2001122769A - Solid preparation and method for improving disintegration/dissolution of solid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve disintegration of a solid preparation and dissolution of a medicine having <=200 deg.C melting point in preparing the solid preparation comprising a first layer containing the medicine and a second layer having a composition different from that of the first layer such as an antacid by formulating the second layer with a lubricant without formulating the lubricant with the first layer. SOLUTION: This solid preparation can not only maintain chemical stability of the medicine but also improve disintegration of the preparation and dissolution of the medicine from the preparation and maintain excellent disintegration and dissolution even in preservation of the preparation even if a component to be reacted with the medicine to be formulated coexists. Consequently the preparation is useful as a solid preparation of oral administration formulated with the medicine especially having <=200 deg.C melting point and is especially useful in the case of coexistence of a substance having reactivity to the medicine such as the antacid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a solid preparation and a method for improving the disintegration and dissolution properties of a solid preparation, and more particularly to the disintegration and dissolution properties of a solid preparation containing a drug having a melting point of 200 ° C. or less in the pharmaceutical field. And a method for improving the disintegration and dissolution of a solid preparation, which can improve the disintegration of the solid preparation and the dissolution of a drug.

[0002]

2. Description of the Related Art In a solid oral pharmaceutical preparation such as a tablet, a drug and a component capable of reacting with the drug often coexist. It is known that the chemical stability of a drug is maintained by blending it to prepare a formulation such as a multilayer tablet or granule.

Further, in the case of a solid preparation containing a drug which causes caking and sintering phenomena, in addition to the above-mentioned problems, there arises a problem of stability concerning physical properties such as deterioration of disintegration and dissolution due to storage. This tendency is remarkable for drugs having a melting point of 200 ° C. or lower.

[0004] As a method of solving the above problems, for example, starch, carboxymethyl cellulose (CMC), CMC
Disintegrants such as calcium, carbonate (NaHCO ₃ , CaCO ₃ ), agar, gelatin powder, crystalline cellulose, croscarmellose, and carmellose calcium are usually used in an amount of 1 to 6
Means such as adding 0% is used.

However, the improvement using only the above-mentioned disintegrant requires the addition of a large amount of disintegrant, which causes problems such as a decrease in ingestibility and portability due to enlargement of the preparation. Therefore, a technique for improving disintegration and dissolution with a small amount of additives has been desired.

The present invention has been made in view of the above circumstances, and is directed to a solid preparation containing a drug having a melting point of 200 ° C. or lower in the pharmaceutical field, wherein the solid preparation has improved disintegration, solubility, and dissolution properties. And a method for improving the disintegration / dissolution property of a solid preparation containing the above drug.

[0007]

Means for Solving the Problems and Embodiments of the Invention The present inventors have conducted intensive studies in order to achieve the above-mentioned object, and as a result, have found that the first layer containing a drug having a melting point of 200 ° C. or lower is mixed. And, in a formulation consisting of a multilayer with a second layer having a composition different from the first layer, when a small amount of a lubricant is blended in the second layer, to prevent a decrease in ingestibility and portability due to enlargement of the formulation, It was found that the amount of various additives was reduced from the viewpoint of safety, and that a solid oral preparation with improved disintegration, dissolution, and dissolution, which fully exhibited the effect of the drug, was obtained.

That is, as apparent from the examples and comparative examples described below, the present inventor has a multilayer structure comprising a first layer containing a drug having a melting point of 200 ° C. or lower and a second layer containing an antacid. In the case of a formulation containing a certain amount of lubricant, a small amount of lubricant was added to the layer containing the antacid (second layer), while the storage test clearly showed a delay in disintegration over time and a decrease in dissolution. In the preparation thus prepared, the delay in disintegration over time and the decrease in dissolution due to storage tests were clearly improved, and it was found that the preparation exhibited a sufficient effect of the drug, and the present invention was accomplished.

Accordingly, the present invention provides a solid preparation comprising a first layer containing a drug having a melting point of 200 ° C. or lower and a composition different from the first layer, particularly a second layer containing an antacid. Without adding a lubricant to the first layer, a solid preparation having improved disintegration and dissolution characterized by being compounded in the second layer, and a first layer containing a drug. A method for improving the disintegrability of a solid preparation having a second layer having a composition different from that of the first layer and the dissolution property of the drug,
A method for improving the disintegration / dissolution property of a solid preparation, characterized by incorporating a lubricant into the second layer.

The present invention will now be described in more detail. The present invention relates to a multi-layer structure comprising a first layer containing a drug having a melting point of 200 ° C. or lower and a second layer having another composition. Tablets, granules, etc., for an internal solid preparation having a dosage form, by blending a lubricant in the second layer, improves the disintegration of the solid preparation over time and the elution of the drug in the solid preparation over time. Is what you do.

The drug of the present invention has a melting point of 200 ° C.
Or less, preferably 175 ° C or less, more preferably 140 ° C or less.

Drugs having a melting point of 200 ° C. or lower include, for example, antipyretic / analgesic drugs such as aspirin, phenylbutazone, acetaminophen, ketoprofen and ibuprofen.
Anti-inflammatory drugs and the like can be mentioned, and these can be used alone or in an appropriate combination of two or more.

The amount of the above drug in the preparation of the present invention is not particularly limited, and can be appropriately selected depending on the effective amount of the above drug.
TC), usually 30 to 95% of the entire first layer
(% By mass, the same applies hereinafter), preferably 60 to 90%. If the amount is too small, it may be necessary to increase the size of the preparation in order to obtain a sufficient drug effect. If the amount is too large, inconvenience may occur in the design of the preparation.

In the case of the present invention, as long as the effects of the present invention are not impaired, additives other than the above-mentioned drugs, which are usually used as necessary, such as excipients, binders, disintegrants, pigments, etc.
Flavoring agents and the like can be used alone or in appropriate combination of two or more kinds, and these components can be used in a usual dose as long as the effects of the present invention are not impaired.

More specifically, the above-mentioned additives include, for example, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, gelatin, polyvinylpyrrolidone, partially pregelatinized starch, crystalline cellulose, gum arabic and the like. Can be mentioned.

Examples of the excipients include lactose, starch (such as corn starch), fructose, glucose, sucrose, lactose, maltose, anhydrous lactose, mannitol, erythritol, sorbitol, sodium ascorbate, cellulose, ethylcellulose, dextran, and macro. Gol, xylitol, citric acid or a salt thereof, calcium hydrogen phosphate, sodium hydrogen phosphate, crystalline cellulose and the like can be mentioned.

Examples of the disintegrant include calcium carboxymethylcellulose, polyvinylpyrrolidone or a crosslinked product thereof, low-substituted hydroxypropylcellulose,
Gelatinized starch, croscarmellose sodium and the like can be mentioned.

The composition of the second layer of the solid preparation of the present invention is not particularly limited as long as it has a composition different from that of the first layer containing the above-mentioned drug. It is desirable to include a component that is desirably blended in another layer, and it is more preferable to blend an antacid as such a component.

The type of the antacid is not particularly limited, and examples thereof include synthetic hydrotalcite,
Magnesium silicate, synthetic aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium carbonate,
Dihydroxyaluminum / aminoacetate (aluminum glycinate), aluminum hydroxide gel (dry aluminum hydroxide gel), aluminum hydroxide / magnesium carbonate mixed dry gel, co-precipitated product of aluminum hydroxide / sodium hydrogen carbonate, aluminum hydroxide A coprecipitation product of calcium carbonate and magnesium carbonate, a coprecipitation product of magnesium hydroxide and potassium aluminum sulfate, magnesium metasilicate aluminate, and the like are preferably used;
Among these, more preferably, synthetic hydrotalcite, dried aluminum hydroxide gel, magnesium carbonate,
Magnesium oxide, dihydroxyaluminum amino acetate (aluminum glycinate) and the like, particularly preferably magnesium carbonate, dried aluminum hydroxide gel,
Magnesium oxide, granules of synthetic hydrotalcite and the like are preferably used. These antacids can be used alone or in an appropriate combination of two or more.

In the case of the present invention, the particle size of the antacid is preferably from 1 to 1500 μm, more preferably from 5 to 800 μm, particularly preferably from 10 to 500 μm. If the particle size is too small, the workability at the time of production may be deteriorated, and if it is too large, it may be difficult to uniformly mix the compound in the antacid layer. In the present invention, the average particle size can be determined from the median by creating a particle size distribution curve by sieving according to the particle size test described in the Japanese Pharmacopoeia, for example, the particle size The average particle size when the ratio of fine particles of about 1 to 50 μm is large is preferably measured by a laser diffraction type particle size distribution analyzer and determined in the same manner as in the above-mentioned sieving method.

When the above-mentioned antacid is blended in the second layer of the present invention, its blending amount is not particularly limited, but the blending ratio (mass ratio) to the above-mentioned drug = the above-mentioned antacid: the above-mentioned drug However, preferably 1: 0.1 to 1:10, more preferably 1: 0.3 to 1: 7, particularly preferably 1: 0.5 to
A ratio of 1: 5 is more preferable because disintegration and dissolution are particularly good. The amount of the antacid in the entire second layer is not particularly limited, and can be appropriately selected depending on the effective amount of the antacid, for example, in the case of over-the-counter (OTC), 30 to 99.999%, preferably 30 to 99%, based on the entire second layer,
More preferably, the content is set to 60 to 95%.

The type of the lubricant compounded in the second layer is not particularly limited, and examples thereof include stearic acid or a salt thereof, palmitic acid or a salt thereof, dimethylpolysiloxane, talc, polyethylene glycol, and the like. Hardened oils, nonionic surfactants such as sucrose fatty acid esters and polyoxysorbitan fatty acid esters, sodium lauryl sulfate, hydrated silicon dioxide, light anhydrous silicic acid, microcrystalline wax, etc. can be preferably used. , Stearic acid or a salt thereof, palmitic acid or a salt thereof, dimethylpolysiloxane, talc, macrogol (4000 or 6000) and the like are particularly preferred. These lubricants can be used alone or in an appropriate combination of two or more.

The particle size of the lubricant is preferably 0.2 to 150 μm, more preferably 0.2 to 150 μm.
5 to 100 μm, particularly preferably 1 to 50 μm in average particle size
It is. Outside of the above range, workability during production may be poor, and it may be difficult to uniformly mix the second layer.

The amount of the lubricant in the preparation of the present invention is not particularly limited, but is preferably 0.001 to 5%, more preferably 0.05 to 5% of the entire second layer. To 2%, particularly preferably 0.1 to 0.5%. If the amount is too small, it may be difficult to sufficiently improve the disintegration and dissolution properties.If the amount is too large, not only the effect of further compounding is not obtained but also inconvenience in the formulation design. May occur.

In the present invention, the above-mentioned lubricant is not blended in the first layer containing the above-mentioned drug. However, depending on the method of adding the lubricant, for example, an external lubrication method, a very small amount may be used. May be present on the surface of the first layer containing the drug. Therefore, the solid preparation in which the trace amount of the lubricant is contained in the first layer in this way is included in the solid preparation of the present invention. However, even in such a preparation, the upper limit of the amount of the lubricant in the first layer is preferably 0.001% or less based on the entire first layer.

In the case of the present invention, as long as the effects of the present invention are not impaired, additives other than the above-mentioned components may be used in the second layer, if necessary, such as excipients, binders, disintegrants, dyes, and the like.
Flavoring agents and the like can be used alone or in appropriate combination of two or more kinds, and these components can be used in a usual dose as long as the effects of the present invention are not impaired.

More specifically, examples of the binder include hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose,
Methylcellulose, gelatin, polyvinylpyrrolidone,
Partially pregelatinized starch, crystalline cellulose, gum arabic and the like can be mentioned.

Examples of the excipients include lactose, starch (such as corn starch), fructose, glucose, sucrose, lactose, maltose, anhydrous lactose, mannitol, erythritol, sorbitol, sodium ascorbate, cellulose, ethylcellulose, dextran, and macro. Gol, xylitol, citric acid or a salt thereof, calcium hydrogen phosphate, sodium hydrogen phosphate, crystalline cellulose and the like.

Examples of the disintegrating agent include carboxymethylcellulose calcium, polyvinylpyrrolidone or a crosslinked product thereof, low-substituted hydroxypropylcellulose, pregelatinized starch, croscarmellose sodium and the like.

The number of layers of the solid preparation of the present invention is not particularly limited as long as it has a multilayer structure of at least two layers including the first layer and the second layer. A two-layer structure including the first layer and the second layer is preferable. The dosage form is not particularly limited as long as it has such a multilayer structure, but is preferably a tablet or a granule as described above.

The method for improving the disintegration / dissolution property of a solid preparation of the present invention comprises mixing the above-mentioned lubricant into the above-mentioned second layer,
It is intended to improve the disintegration of a solid preparation having the first layer and the second layer and the dissolution of the drug.

The method of the present invention will be described in more detail. As the raw material mixture for the first layer, the above-mentioned additives and the like are added and mixed as needed with the above-mentioned drug, while the raw material for the second layer is mixed. As a mixture, for example, adding and mixing the above-mentioned antacid and the above-mentioned additives as needed, without adding the lubricant to the raw material mixture of the first layer, the raw material mixture of the second layer And mix.

When a tablet is prepared as the solid preparation, the raw material mixture of the first layer component and the raw material mixture of the second layer component are mixed using a commonly used tableting machine.
A layered tablet (the solid preparation of the present invention) can be obtained by tableting at a normal tableting pressure by an ordinary method. When the solid preparation of the present invention is prepared as a tablet, the tablet can be used as it is, but can be coated with a polymer compound film or a sugar-coated tablet.

On the other hand, when granules are prepared as the solid preparation, the composition is not particularly limited as long as it is a layer containing the first layer and the second layer. The raw material mixture of the first layer component is granulated by, for example, a known granulation method to prepare a first layer, and the raw material mixture of the second layer component containing the lubricant in the first layer is prepared by a known method. To prepare layered granules. When the solid preparation of the present invention is prepared as granules, it can be used as it is,
Further, the surface may be coated by spraying a polymer compound or a sugar solution.

The solid preparation of the present invention can be prepared by the above-mentioned method, and its use and usage are excellent in disintegration and disintegration by taking the usual solid preparation containing the compounded drug by a conventional method. Shows the dissolution property of the drug, and the drug effect of the compounded drug is promptly exhibited.

[0036]

According to the present invention, even when a component having a melting point of 200 ° C. or lower and reacting with a drug coexists, not only can the chemical stability of the drug be maintained, but also the Disintegration and dissolution of the drug from the preparation can be improved, and excellent disintegration and dissolution can be maintained even when the preparation is stored. Therefore, the present invention is particularly useful for an oral solid preparation in which a drug having a melting point of 200 ° C. or lower is reactive with the drug, for example, an antacid.

[0037]

EXAMPLES The present invention will be described below in detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. In the following example, tableting was performed using a tableting machine (manufactured by Kikusui Seisakusho: Libra) with a tableting pressure of about 1
Tablets having a diameter of 10 mm were obtained at 200 kgf (# 11760N).

Example 1 Aspirin (2970 g) and corn starch (330.75 g) were mixed with a V-type mixer (Tokuju Seisakusho,
V-5) and mixed for 10 minutes. This mixture is subjected to a dry roll compression granulator (WP-50N type; ALEXA).
The product was roll-compressed using NDERWERK) and sized using a crushing-type granulator (T54S type; manufactured by Nippon Granulator) to prepare granules A having an average particle size of 1200 μm.

On the other hand, synthetic hydrotalcite was spray-granulated with a spray granulator (Okawara Kakoki Co., Ltd., spray dryer L-8 type) to produce a granulated product having an average particle size of 246 μm. 1000 g of this granulated product and 180 g of corn starch (average particle size: 14.5 μm) were mixed with a V-type mixer (Tokuju Seisakusho: V
After mixing for 10 minutes, 1.5 g of magnesium stearate (average particle size: 8.1 μm) was added and mixed for 5 minutes to prepare mixed granules B. The granules A and B were placed in a mortar and tableted to obtain uncoated laminated tablets in which the composition per tablet was the following composition of the laminated preparation. Further, 1000 g of the tablet was dissolved in a water composition containing the following composition of the film coating agent, and a 12% solution was used as a coating solution. Coater 30) to obtain a coated laminated tablet.

<Blended Composition of Laminated Preparation> Blended Components Blended Amount (mg) First Layer Aspirin 330 Corn Starch 36.75 Second Layer Synthetic Hydrotalcite (Average Particle Size 246 μm) 100 Corn Starch (Average Particle Size 14.5 μm) 18 Magnesium stearate (average particle size 8.1 μm) 0.15 Total 484.9

<Blending Composition of Film Coating Agent> Blending Components Blending Amount (g) Hydroxypropylmethylcellulose 2910 75.5 Macrogol 6000 11.9 Titanium oxide 12.6 Total 100

Example 2 Granules A were prepared by the same production method as in Example 1 above. On the other hand, corn starch 30
After adding 3000 g of water to 0 g and uniformly dispersing the mixture and heating to form a paste, the mixture is uniformly added to 3000 g of synthetic hydrotalcite and subjected to wet stirring granulation (high speed mixer FS-10, manufactured by Fukae Kogyo). After drying and sizing, granules having an average particle size of 350 μm were obtained. 200 g of corn starch (average particle size 14.5 μm) was weighed into 2750 g of the granules in a V-type mixer (V-5 type, Tokuju Seisakusho), mixed for 10 minutes, and then magnesium stearate (average particle size 8.1 μm).
m) 3.75 g was added and mixed for 5 minutes to prepare mixed granule C. The granules A and C were placed in a mortar and tabletted to obtain uncoated laminated tablets in which the composition per tablet was the following composition of the laminated preparation. In addition, 1000 g of this tablet
Then, a film coating having the same composition (Hicoater 30, Freund Co., Ltd.) was obtained by the same operation method as in Example 1.
Mold) to obtain a coated laminated tablet.

<Blending Composition of Laminated Preparation> Blending Components Blending Amount (mg) First Layer Aspirin 330 Corn Starch 36.75 Second Layer Synthetic Hydrotalcite (Average Particle Size 12 μm) 100 Corn Starch (Average Particle Size 14.5 μm) 18 Magnesium stearate (average particle size 8.1 μm) 0.15 Total 484.9

Example 3 Granules A were produced by the same production method as in Example 1 above. On the other hand, magnesium carbonate was converted to a dry roll compression granulator (WP-50N type; ALEXAN).
The resulting mixture was roll-compressed using a DERWERK (manufactured by DERWERK) and sized using a crushing-type granulator (Model T54S; manufactured by Nippon Granulator) to produce granules having an average particle size of 280 μm. 1000 g of this granulated product, corn starch (average particle size 14.5μ)
m) 180 g was weighed into a V-type mixer (V-5 type), mixed for 10 minutes, added with 1.5 g of magnesium stearate (average particle size: 8.1 μm), and mixed for 5 minutes. The mixed granule D was produced. The granules A and D were placed in a die and tableted to obtain uncoated laminated tablets in which the composition per tablet was the following composition of the laminated preparation. In addition, 1000 g of the tablet was coated with the same composition as in Example 1 by film coating (Freund Co., Ltd., Hicoater Model 30) to obtain a coated laminated tablet.

<Blending composition of laminated preparation> Blending components Blending amount (mg) First layer Aspirin 330 Corn starch 36.75 Second layer Magnesium carbonate (average particle size 280 μm) 100 Corn starch (average particle size 14.5 μm) 18 Stearic acid Magnesium (average particle size 8.1 μm) 0.15 Total 484.9

Example 4 Granules A were produced in the same manner as in Example 1 above. On the other hand, the synthetic hydrotalcite was spray-granulated in the same manner as in Example 1, and the average particle size was 246 μm.
Was produced. 600 g of crystalline cellulose was added to 3000 g of the granulated product, and a V-type mixer (V-5, Tokuju Seisakusho)
After mixing for 10 minutes, 5.4 g of magnesium stearate (average particle size: 8.1 μm) was added and mixed for 5 minutes to prepare mixed granules E. The granules A and E were placed in a mortar and tableted to give uncoated laminated tablets in which the composition per tablet was the following composition of the laminated preparation. Also,
A 1000 g portion of each tablet was taken, and a film coating having the same composition (Freund,
High Coater 30) to obtain a coated laminated tablet.

<Blended Composition of Laminated Preparation> Blended Components Blended Amount (mg) First Layer Aspirin 330 Corn Starch 36.75 Second Layer Synthetic Hydrotalcite (Average Particle Size 246 μm) 100 Crystalline Cellulose 20 Magnesium Stearate (Average Particle Size) 8.1 μm) 0.18 Total 486.93

Example 5 Granules A were produced by the same production method as in Example 1 above. On the other hand, the synthetic hydrotalcite was spray-granulated in the same manner as in Example 1 to produce a granulated product having an average particle size of 50 μm. Lactose (DM)
V200M) 450 g and carboxymethylcellulose 300 g were added and mixed with a V-type mixer (Tokuju Seisakusho, V-5 type) for 10 minutes. Then, 5.7 g of magnesium stearate (average particle size 8.1 μm) was added, and the mixture was added for 5 minutes. By mixing, a mixed granule F was prepared. The granules A and F were placed in a mortar and tableted to obtain uncoated laminated tablets in which the composition per tablet was the following composition of the laminated preparation. In addition, 1000 g of the tablet was coated with the same composition as in Example 1 by film coating (Freund Co., Ltd., Hicoater Model 30) to obtain a coated laminated tablet.

<Blending Composition of Laminated Preparation> Blending Component Blending Amount (mg) First Layer Aspirin 330 Corn Starch 36.75 Second Layer Synthetic Hydrotalcite (Average Particle Size 50 μm) 100 Lactose 15 Carboxymethyl Cellulose 10 Magnesium Stearate (Average) (Particle size: 8.1 μm) 0.19 total 491.94

Example 6 Lactose (600 g) was added to 3000 g of ibuprofen, and the mixture was granulated with an aqueous solution of hydroxypropylcellulose (Freund, Spiral Flow SF).
C-5 type), weighed 2976 g, added 480 g of lactose, weighed it into a V-type mixer (V-5 type, Tokuju Seisakusho), and mixed for 10 minutes to prepare mixed granules G.

On the other hand, aluminum glycinate 1500
g and magnesium oxide (1500 g) were weighed in a stirring granulator, and 1890 g of water was added to 210 g of gelatin to uniformly disperse the mixture, and the solution obtained by heating and dissolving the mixture was added uniformly, and the mixture was wet-stirred and granulated (High Speed Mixer FS- 10 type)
The resulting mixture was dried and sized to obtain granules having an average particle size of 420 μm. After weighing 280 g of crystalline cellulose and 280 g of carboxymethyl cellulose in 2996 g of the granules in a V-type mixer (V-5 type, Tokuju Seisakusho), and mixing for 10 minutes,
71.12 g of talc (average particle size: 18.3 μm) was added,
After mixing for 5 minutes, mixed granules H were prepared. The above granules G,
H was placed in a mortar and tableted to obtain uncoated laminated tablets in which the composition per tablet was the following composition of the laminated preparation. In addition, 1000 g of the tablet was coated with the same composition as in Example 1 by film coating (Freund Co., Ltd., Hicoater Model 30) to obtain a coated laminated tablet.

<Blending Composition of Laminated Preparation> Blending Component Blending Amount (mg) First Layer Ibuprofen 75 Lactose 30 Hydroxypropylcellulose 3 Second Layer Aluminum Glycinate (Average Particle Size 12 μm) 50 Magnesium Oxide (Average Particle Size 30 μm) 50 Gelatin 7 Crystalline cellulose 10 Carboxymethylcellulose 10 Talc (average particle size 18.3 μm) 2.54 Total 237.54

Example 7 Acetaminophen 3000
300 g of lactose was added to the resulting mixture, and granules I (Freund, Spiral Flow SFC-5) were prepared using an aqueous solution of hydroxypropylcellulose.

On the other hand, dried aluminum hydroxide gel 240
0 g and 400 g of corn starch are weighed in a stirring granulator,
1800 g of water was added to 200 g of gelatin, and the mixture was dispersed uniformly, and the solution obtained by heating and dissolving was uniformly added.
The mixture was granulated, dried and sized to obtain granules having an average particle size of 450 μm. To 1500 g of the granules, 30 g of microcrystalline wax (average particle size: 48 μm) was weighed into a V-type mixer (V-5 type, Tokuju Seisakusho) and mixed for 5 minutes to prepare mixed granules J. Take the granules I and J in a mortar, press
An uncoated laminated tablet was obtained in which the composition per tablet was the following composition of the laminated preparation. In addition, this tablet 100
0 g, and the same operation as in Example 1 was performed to obtain a film coating having the same composition (Freund Co., Ltd., Hicoater 3).
0) to obtain a coated laminated tablet.

<Blending composition of laminated preparation> Blending components Blending amount (mg) First layer Acetaminophen 300 Lactose 30 Hydroxypropylcellulose 10 Second layer Dry aluminum hydroxide gel (average particle size 20 μm) 120 Corn starch 20 Gelatin 10 Micro Crystallin wax (average particle size 48 μm) 3 total 493

Example 8 500 g of lactose was added to 2500 g of ketoprofen, and the mixture was granulated with an aqueous solution of hydroxypropylcellulose (Freund, Spiral Flow SF).
C-5) to produce granules K.

On the other hand, magnesium oxide was subjected to dry granulation in the same manner as in Example 3 to produce granules having an average particle size of 328 μm. 3000 g of these granules and 600 g of corn starch
Is weighed into a V-type mixer (V-5 type, Tokuju Seisakusho).
After mixing for 0 minutes, 5.5 g of calcium stearate (average particle size: 10.2 μm) was added and mixed for 5 minutes to prepare mixed granules L. The granules K and L were placed in a mortar and tabletted to obtain uncoated laminated tablets in which the composition per tablet was the following composition of the laminated preparation. In addition, this tablet 1
A 000 g portion was subjected to a film coating (Freund Co., Ltd., Hicoater 30 type) having the same composition by the same operation method as in Example 1 to obtain a coated laminated tablet.

<Blending Composition of Laminated Preparation> Blending Components Blending Amount (mg) First Layer Ketoprofen 50 Lactose 10 Hydroxypropylcellulose 2.4 Second Layer Magnesium Oxide (Average Particle Size 328 μm) 60 Corn Starch 12 Calcium Stearate (Average Particle Size) 10.2 μm) 0.11 Total 134.51

Comparative Example 1 Granules A were prepared in the same manner as in Example 1. Magnesium stearate (average particle size: 8.1 μm) was added to 256.25 g of the granules A.
Add 22g and mix for 5 minutes (V-5
Mold) and mixed granules M were prepared.

On the other hand, the synthetic hydrotalcite was spray-granulated by a spray granulator (spray dryer L-8, manufactured by Okawara Kakohki Co., Ltd.) to produce a granulated product having an average particle size of 246 μm. 1000 g of this granulated product and 180 g of corn starch (average particle size 14.5 μm) were mixed with a V-type mixer (Tokuju Seisakusho, V
After mixing for 10 minutes, 1.5 g of magnesium stearate (average particle size: 8.1 μm) was added and mixed for 5 minutes to prepare mixed granules B. The granules M and B were placed in a mortar and compressed into tablets to obtain uncoated laminated tablets in which the composition per tablet was the following composition of the laminated preparation. In addition, 1000 g of the tablet was coated with the same composition as in Example 1 by film coating (Freund Co., Ltd., Hicoater Model 30) to obtain a coated laminated tablet.

<Blended Composition of Laminated Preparation> Blended Components Blended Amount (mg) First Layer Aspirin 330 Corn Starch 36.75 Magnesium Stearate (Average Particle Size 8.1 μm) 0.46 Second Layer Synthetic Hydrotalcite (Average Particle) Diameter 246 μm) 100 Corn starch (average particle size 14.5 μm) 18 Magnesium stearate (average particle size 8.1 μm) 0.15 Total 485.36

Comparative Example 2 A mixed granule M was prepared in the same manner as in Comparative Example 1. On the other hand, synthetic hydrotalcite was spray-granulated by a spray granulator (spray dryer L-8, manufactured by Okawara Kakohki Co., Ltd.) to produce a granulated product having an average particle size of 246 μm. 1000 g of this granulated product and 180 g of corn starch (average particle size: 14.5 μm) were weighed into a V-type mixer (V-5 type, Tokuju Seisakusho), and mixed for 10 minutes to prepare mixed granules N. The granules M and N were placed in a die and tableted to obtain uncoated laminated tablets in which the composition per tablet was the following composition of the laminated preparation. Also,
A 1000 g portion of each tablet was taken, and a film coating having the same composition (Freund,
High Coater 30) to obtain a coated laminated tablet.

<Blended Composition of Laminated Preparation> Blended Component Blended Amount (mg) First Layer Aspirin 330 Corn Starch 36.75 Magnesium Stearate (Average Particle Size 8.1 μm) 0.46 Second Layer Synthetic Hydrotalcite (Average Particle) Diameter 246 μm) 100 corn starch (average particle size 14.5 μm) 18 total 485.21

Comparative Example 3 A non-coated laminated tablet was obtained in the same manner as in Comparative Example 2 except that the lubricant was not blended in the first layer. . In addition, 1000 g of the tablet was coated with the same composition as in Example 1 by film coating (Freund Co., Ltd., Hicoater Model 30) to obtain a coated laminated tablet.

<Blended Composition of Laminated Preparation> Blended Components Blended Amount (mg) First Layer Aspirin 330 Corn Starch 36.75 Second Layer Synthetic Hydrotalcite (Average Particle Size 246 μm) 100 Corn Starch (Average Particle Size 14.5 μm) 18 Total 484.75

Each of the above tablets was packaged in a PTP package (packaging material VSL: polyvinyl chloride, polyvinylidene composite sheet) and stored for 3 to 6 months at room temperature and at 40 ° C. and 75% RH. The disintegration time was measured by a disintegration test of the Japanese Pharmacopoeia, and the disintegrability of the stored product was evaluated according to the following evaluation criteria. Table 1 shows the results.

<Evaluation criteria for disintegration time> Less than 15 minutes: ◎ Less than 15 to 30 minutes: ○ Less than 30 to 60 minutes: Δ More than 60 minutes: ×

[0068]

[Table 1]

Further, tablets prepared in the same manner as in the above Examples 1 to 8 except that a sugar coating was applied instead of the film coating, and
8 tablets instead of PTP packaging material of VSL material, COC
PTP with material containing (cycloolefin copolymer)
As a result of the same storage test as described above for the packaged products, all were similarly good.

According to the above results, an antacid (synthetic hydrotalcite) was used as a first layer containing a drug and a layer containing a drug (aspirin) having a melting point of 200 ° C. or less and a second layer having another composition. In the solid preparation of the present invention comprising a multi-layer of layers containing), a lubricant is added to the second layer containing the antacid, and no lubricant is added to the first layer containing the drug. It can be seen that the disintegration of the tablet was significantly improved. And by improving the disintegration in this way, the dissolution of the drug from the preparation is also improved.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Seiji Ito 1-3-7 Honjo, Sumida-ku, Tokyo Inside Lion Corporation (72) Inventor Shuichi Ueda 1-3-7, Honjo, Sumida-ku, Tokyo F term in Lion Corporation (reference) 4C076 AA31 AA40 CC01 CC05 CC16 CC50 DD25 DD29H DD41C EE23H EE32H EE38 FF06 FF09 FF36

Claims (3)

[Claims] 1. A solid preparation comprising a first layer containing a drug having a melting point of 200 ° C. or lower and a second layer having a composition different from that of the first layer, wherein a lubricant is added to the first layer. A solid preparation having improved disintegration and dissolution properties, wherein the solid preparation is blended in the second layer without being blended into the second layer. 2. The solid preparation according to claim 1, wherein the second layer contains an antacid. 3. Improving the disintegration property of a solid preparation having a first layer containing a drug having a melting point of 200 ° C. or lower and a second layer having a composition different from that of the first layer and the dissolution property of the drug. A method for improving the disintegration / dissolution property of a solid preparation, which comprises adding a lubricant to the second layer.